The repair of damaged tissues subsequent to a disease, a trauma or age increasingly uses stem or progenitor cells which retain the ability to differentiate into various cell types. These cells constitute a reservoir capable of renewing tissues in order to restore biological functions. Mesenchymal stem cells, for example, can give osteoblasts, chondrocytes, adipocytes, or stromal cells which are a support for hematoporesis.
The techniques which make it possible to direct these cells toward a chosen phenotype are generally laborious (transformation of cells using expression vectors and the need to express several genes) and alternative solutions such as the use of small synthetic differentiation-inducing molecules would constitute a promising approach.
Among the disorders resulting from a cell differentiation defect are those linked to a dysfunction of osteoblast differentiation.
Bone is continually renewed during life by means of a complex process involving resorption by osteoclasts and formation by osteoblasts.
Osteoblast precursors are pluripotent cells also known as mesenchymal stem cells. However, the mechanisms which allow these cells to differentiate into the osteoblast lineage are complex and are of great importance in the understanding of bone development. In addition, the identification of molecules which would induce osteoblast differentiation and would stimulate their osteogenic activity would represent a therapeutic approach in the treatment of bone diseases.
Indeed, many diseases are caused by dysregulation of osteoblast function or differentiation and also functional imbalances between osteoblasts and osteoclasts. The pathological condition most widely studied—since it represents a major economic challenge—is osteoporosis; osteoporosis is characterized by an excessive brittleness of the skeleton due to a decrease in bone mass and to modification of the bone microarchitecture. The solidity of bone results from an equilibrium between the action of two types of bone cells: osteoblasts which solidify bone and osteoclasts (responsible for bone resorption) which embrittle bones. A dominant activity of osteoclasts leads to osteoporosis which can result either from insufficient bone material at the end of growth, or from excessive bone loss during aging. The prevention of osteoporosis can take place via the reduction of a physiological precursor phenomenon, osteopenia (decrease in bone density) which can, before osteoporosis, lead to bone rarefaction disorders and to embrittlement of the bone tissue.
Other pathological conditions are associated with dysfunctions that induce a loss of bone mass; mention may be made of:                osteogenesis imperfecta: this disease is also known as “brittle bone disease” and groups together diseases characterized by excessive bone brittleness due to a congenital defect in the development of the collagen fibers of the connective tissue which forms the framework of the bone. All types are characterized by an extreme bone brittleness, which is the most typical sign of the disease;        hypercalcemia;        hyperparathyroidism;        osteomalacia; which corresponds to bone decalcification induced by a mineralization defect (lack of calcium and phosphate ions) of the protein framework of the skeleton;        osteonecrosis; which covers ailments defined by the death of the cells of the bone tissue;        Paget's disease of bone (osteitis deformans); osteopathy, localized in one or more bones, characterized by excessive bone remodeling resulting in progressive hypertrophy of bone pieces and in considerable abnormalities of the bone microarchitecture;        rheumatoid arthritis;        inflammatory arthritis;        osteomyelitis;        paradontitis;        bone metastases.        
Renewal of the bone tissue may also be necessary in situations where it is sought to accelerate bone repair, such as fractures, plastic surgery or the insertion of implants, in particular dental implants.
Osteoblast differentiation is influenced by many signaling pathways, including, for example, the TGB-β (transforming growth factor β1), Hedgehog (Hh) protein, Wnt, FGF (fibroblast growth factor), IGF1 (insulin-like growth factor 1) or BMP (bone morphogenetic protein) pathways (Centrella et al. 1994; Yamaguchi et al. 2000; van der Horst et al. 2003; Fromigue et al. 2004; Hu et al. 2005).
Although BMPs have been used successfully (Johnson and Urist 2000), they are expensive and the doses required in order to carry out efficient cell differentiation are well above the acceptable physiological thresholds. An alternative would be the use of small molecules which make it possible to modulate BMP activity in vivo (Yu et al. 2008).
TGF-β has also been described as a major participant in regulating the balance of the activity between osteoclasts and osteoblasts. Recently, pharmacological inhibitors of its receptor have shown a stimulatory activity on osteoblasts and an inhibitory activity on osteoclasts (Mohammad et al. 2009).
The role of IGF1 has been well studied, but the use of recombinant human IGF1, despite an influence on bone metabolism, has some disadvantages. It does not specifically target the skeleton and causes side effects which limit its use for bone diseases.
The Hedgehog signaling molecule plays a fundamental role in the morphogenesis of numerous tissues, including bone, and also in cell proliferation, and appears to be involved in tissue maintenance and repair in adults (see the reviews by Ingham and McMahon 2001; Wechsler-Reya and Scott 2001; Marti and Bovolenta 2002; Lum and Beachy 2004; Varjosalo and Taipale 2008).
Stimulation of the Hedgehog pathway makes it possible to induce osteogenesis in various models. Several agonist molecules have been studied:                the Hedgehog proteins and derived polypeptides which stimulate osteoblast differentiation by acting on the Patched protein (Spinella-Jaegle et al. 2001; Guan et al. 2009);        purmorphamine which makes it possible to activate human osteoblasts in culture (Wu et al. 2004; Beloti et al. 2005);        small organic molecules such as SAG (Chen et al. 2002);        the Hh Ag1.2 molecules (Frank-Kamenetsky et al. 2002);        oxysterol derivatives (Corcoran and Scott 2006; Amantea et al. 2008) which induce osteoblast differentiation and bone formation (Aghaloo et al. 2007; Dwyer et al. 2007; Yu et al. 2008).        
However, it remains useful to identify novel molecules which make it possible to modulate cell differentiation, in particular molecules which have an osteogenic activity, and which make it possible to ally good activity and a limited cost; such molecules would be of particular interest for treating bone-related pathological conditions.